PROJECT SUMMARY/ABSTRACT Rett syndrome (RTT), an X-linked autism spectrum disorder, is a devastating childhood disability and has a tremendous impact on individuals (1:10,000 births), their families and society. The majority of RTT cases are caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). RTT girls are born without any obvious problems but abruptly develop a host of neurological deficits, including irregular breathing, loss of purposeful hand movement and speech, seizures, and intellectual disability. Among these symptoms, motor dysfunction and deficits in attention-related behavioral shifting are the most profound, bearing resemblance to several brain disorders of basal ganglia origin. Disease-modifying therapies that are designed for the treatment of RTT require a clear understanding of the underlying pathophysiology at the molecular, cellular, and network levels. Dysfunction of the striatum, where most inputs enter the basal ganglia, may play a significant role in RTT pathogenesis. The striatum receives glutamatergic excitatory projections from the thalamus, which integrate and modulate cortical inputs for proper striatal output. Our preliminary data demonstrate altered function and plasticity of thalamo-striatal synapses in Mecp2 knockout (KO) mice, which may contribute to dysfunction of cortico-striatal synaptic. Our hypothesis is that altered thalamo-striatal synaptic function in Mecp2 KO mice disintegrates the striatal role in integrating cortical inputs. We propose two Specific Aims: (1) characterize thalamic neurons and their synaptic projections to the dorsal striatum of Mecp2 KO mice; (2) test whether the impact of thalamic inputs on cortico-striatal system in dorsal striatum is impaired in Mecp2 KO mice. We anticipate that these experiments will yield novel information regarding the consequences of MeCP2 loss on thalamo-striatal synaptic transmission and plasticity, as well as on its integration and control of cortico-striatal connections. These findings will uncover fundamental brain mechanisms involved in RTT neuropathology, and aid to develop and test novel therapeutic approaches. Our studies will also have deep implications for the understanding and treatment of other neurological disorders with common symptoms and neural substrates, including Huntington and Parkinson diseases, as well as Tourette and Angelman syndromes.